Process for the production of nuclearly fluorinated pyridines, quinolines, isoquinolines, and pyrimidines



Patented Mar-l4, 1961 PROCESS FOR THE PRODUCTION OF NUCLEARLY FLUORINATED PYRIDINFE, QUINOLINES, ISO- QUINOLINES, AND PYRIMIDINES 1 Alfons Dorlars, Leverkusen, Germany, assignor to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen,

a corporation of Germany This invenion relates to nuclearly fluorinated N-heterocyclic compounds and to a process for their production.

It has been found that nuclearly fluorinated N-heterocyclic compounds are obtained if N-heterocyclic compounds which are substituted in the nitrogenous ring in the a-position or 'y-position by one or more hydroxy groups, and if desired contain further substituents, or their tautomeric carbonyl compounds are reacted with 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride).

Heterocyclic compounds suitable for the process of the invention are for example 2-hydroxy-pyridine (vi-pyridone), 2-hydroxy-quinoline and its nuclearly substituted derivatives, such as for example 6-chloro-carbostyrile or 6-methoxy-carbostyrile, 4-hydroxy-quinoline (quinolone), 4-methyl-2-hydroxyquin0line (lepidone), 2,4-dihydroxyquinoline, 2-methyl-4-hydroxy-quinoline (quinaldone), 1,3-dihydroxy-isoquinoline, 2- or 4-hydroxy-pyrimidine and others. i

The 2,4,6-trifluoro-1,3,5-triazine can be obtained by, for example, reacting cyanuric chloride, cyanuric 'bromide or cyanuric iodide with hydrogen fluoride or with neutral or acid fluorides.

When using the process according to the invention, it is necessary to use at least /3 mol of cyanuric fluoride per mol of hydroxyl group for the reaction. It is, however, frequently advisable to use an excess of cyanuric fluoride. The reaction is in this case preferably carried out in an inert solvent or diluent, such as for example benzine, benzene, xylene, chlorobenzene, tetrachlorethane or also excess cyanuric fluoride. Temperatures in the range between 50 and 220 C. are generally particularly suitable. If it is desired, the reaction can also be carried out under pressure. The working up of the resulting reaction products can take place after removal of any solvent or excess cyanuric fluoride which may be present and after hydrolysis of any fluoro-triazines which may still be present, the removal thereof being effected by known methods, for example by steam distillation, extraction or crystallisation.

The fluorine compounds which can be produced by the new process can be used as plant protecting agents or for the production of dyes, pharmaceutical products or plantprotecting agents.

The following examples further illustrate the invention without, in any way, limiting it thereto.

Example 1 A mixture of 95.5 grams (0.6 mol) of lepidone-(Z) and 54 grams (0.4 mol) of cyanuric fluoride are heated in an autoclave for 1 /2 hours to 175 C. The mixture is allowed to cool, the semi-solid reaction product is stirred with excess soda solution and subjected to steam distillation. The colorless oil distilling over' is separated from the distillate, dried with anhydrous sodium sulfate and distilled at reduced pressure. There is obtained a good yield of 2-fluoro-lepidine with a B.P. of 140 C.

C H FN (molecular weight 161.2): Calculated: C,

H, 5.18; F, 11.70; N, 8.85.

' Example 2 48 grams (0.3 mol) of quinaldone-(4) are heated with 27 grams (0.2 mol) of cyanuric fluoride in a glass flask with exclusion of moisture for 1 to 1 /2 hours on a water bath to to C. The brown-colored reaction product is worked up as indicated in Example I. The 4-fluoro-quinaldine is obtained by steam distillation in the form of its hydrate as a crystalline colorless mass. It is filtered oil, dissolved in ether, the solution is dried with sodium sulfate and the ether is distilled off. The residual oil is purified by distillation; B.P. of 114 C.

On standing in moist air, the liquid 4-fluoro-quinaldine gradually changes into its crystallised hydrate.

C H FN (molecular weight 161.2): Calculated: C, 74.50; H, 5.00; F, 11.79; N, 8.69. Found: C, 74.61,- H, 5.08; F, 11.68; N, 8.71.

An aqueous dilution of the above compound was prepared by mixing the 4-fluoro-quinaldine with the same amount of dimethylformamide as an auxiliary solvent, adding thereto 20% by weight referred to the 4-fiuoroquinaldine of a commercial emulsifier consisting of a benzyl hydroxy polyglycol ether containing about 10 to 15 glycol residues. This mixture was diluted with water to a 0.2% by weight content of the 4-fluoro-quinaldine. The activtiy of the 4-fluoro-quinaldine as plant protecting agent was then tested against spider mites in the following manner:

Bean plants hight were 0.2% plants have been infested heavily with the two-spotted spider (species Tetranychus telarius). An evaluation was carried out after 24 hours whereby a killing rate of 90% was observed. 4

sprayed drip wet with the above-described Example 3 28.5 grams (0.3 mol pyridone-(2) are heated with 20.3 'grams (0.15 mol) of cyanuric fluoride for 1 /2 hours to to C. in an autoclave (volume 200 m1.). A pressure of approximately 10 atm. is adjusted. Alter cooling, the semi-solid residue is made alkaline with 10% sodium carbonate solution and subjected to steam distillation. The colorless oil distilling over is extracted with ether, the ethereal phase is separated and dried with anhydrous sodium sulfate. After evaporating the ether, the residual crude 2-fluoro-pyn'dine is distilled. In this way, it is obtained in a pure form as a colorless oil with a B.P. of 126 C.

Example 4 48.3 grams (0.3 mol) of 4-hydroxy-quinolone-(2) are mol) of cyanuric fluoride in heated with 54 grams (0.4 an autoclave for 1 hour at C. After cooling, the reaction product is triturated with Example 5 48.3 grams (0.3 mol) of l,3-dihydroxy-isoquinoline are heated at 165 C. for 1 hour in an autoclave with 54 grams (0.4 mol) of cyanuric fluoride. The reaction mix- 1,3-difluoro-isoquinoline is obtained as a colorless oil which at 11.79; N, 8.69. Found: c, 74.20; i

(Plzaseolus vulgaris) of about 50 inches aqueous solution of 4-fluoro-quinaldine. The bean once solidifies as crystals. 13.12 of 112 C., melting point 57' C.

C H F N (molecular weight 165.1): Calculated: C, 65.47; H, 3.05; F, 23.02; N, 8.48. Found: C, 65.42; H, 3.15; F, 23.07; N, 8.48.

I claim:

1. Process for the production of N-heterocyclic compounds fiuorinated in the nitrogen-containing ring, said fluorine atoms occupying at least one of the aand 7-p0- sitions relative to said nitrogen atom, which comprises heating an N-heterocyclic compound which is a member selected from the group consisting of Z-hydroxy-pyridine, 2-hydroxy-quinoline, 4-hydroxy-quinoline, 4-methyl-2- hydroxy-quinoline, 2,4-dihydroxy-quinoline, 2-methyl-4- hydroxy-quinoline, 1,3 dihydroxy-iso-quinoline, 2-hydroXy-pyrimidine, 4-hydroxy-pyrimidine, 2 hydroxy 6- chloro-quinoline, Z-hydroxy 6 methoxy-quinoline and Z-hydroxy-pyridine with an amount of 2,4,6-trifiuoro-1,3, triazine, representing at least one third of a mol per mol of each hydroxyl group to be replaced in said N-heterocyclic compound, at a temperature of from about 40 to 220 C., and recovering the corresponding nuclearly fluorinated N-teterocyclic compound formed by replacement of at least one of the hydroxyl groups with fluorine.

2. Process according to claim 1, in which the heating is efiected at a temperature between 50 and 220 C.

to claim 1, in which the heating of an inert hydrocarbon 3. Process according is effected in the presence solvent.

4. Process according to claim 1, in which an excess of 2,4,6-trifluoro-1,3,5-triazine is used.

5. Process according to claim 1, in which said N-heterocyclic group member is present in its tautomeric form.

References Cited in the file of this patent UNITED STATES PATENTS 2,742,479 Bavley et al. Apr. 17, 1956 2,802,005 Heidelberger et al. Aug. 6, 1957 2,810,706 Frazier et al. Oct. 22, 1957 2,838,514 Surrey et al. June 10, 1958 2,875,126 Hodel et al Feb. 24, 1959 OTHER REFERENCES Society,

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2 975, 179 March 14, 1961 Alfons D'orlars It is hereby certified that error ai'i aars in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below Column 1, line 72, and column 2, lines 17 and 63, for "3'7;

first occurrence, each occurrence read Same column 2 line 28, for --'.'activtiy" read activity column 3 line 3, for "2", first occurrence read line 23, for "N- teterocyclic" read 'Nheterocyclic Signed and sealed this 3rd day of October 1961..

(SEAL) Attest:

ERNEST W. SWIDER A DAVID L.- LADD Attesting Officer Commissioner of Patents USCOMM-DIC" 

1. PROCESS FOR THE PRODUCTION OF N-HETEROCYCLIC COMPOUNDS FLUORINATED IN THE NITROGEN-CONTAINING RING, SAID FLUORINE ATOMS OCCUPYING AT LEAST ONE OF THE A-AND Y-POSITIONS RELATIVE TO SAID NITROGEN ATOM, WHICH COMPRISES HEATING AN N-HETEROCYCLIC COMPOUND WHICH IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF 2-HYDROXY-PYRIDINE, 2-HYDROXY-QUINOLINE, 4-HYDROXY-QUINOLINE, 4-METHYL-2HYDROXY-QUINOLINE, 2-4-DIHYDROXY-QUINOLINE, 2-METHYL-4HYDROXY-QUINOLINE, 1,3 - DIHYDROXY-ISO-QUINOLINE, 2-HYDROXY-PYRIMIDINE, 4-HYDROXY-PYRIMIDINE, 2 - HYDROXY - 6CHLORO-QUINOLINE, 2-HYDROXY - 6 - METHOXY-QUINOLINE AND 2-HYDROXY-PYRIDINE WITH AN AMOUNT OF 2,4,6-TRIFLUORO-1,3, 5-TRIAZINE, REPRESENTING AT LEAST ONE THIRD OF A MOL PER MOL OF EACH HYDROXYL GROUP TO BE REPLACED IN SAID N-HETEROCYCLIC COMPOUND, AT A TEMPERATURE OF FROM ABOUT 40 TO 220*C., AND RECOVERING THE CORRESPONDING NUCLEARLY FLUORINATED N-TELEROCYCLIC COMPOUND FORMED BY REPLACEMENT OF AT LEAST ONE OF THE HYDROXYL GROUPS WITH FLUORINE. 